title: Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase.
abstract: The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C-nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme.
authors.affiliation: Carbohydrate Chemistry, Industrial Research Ltd, Lower Hutt 5040, New Zealand.
authors.forename: Keith
authors.initials: K
authors.lastname: Clinch
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Crump
authors.forename: Gary B
authors.initials: GB
authors.lastname: Evans
authors.forename: Keith Z
authors.initials: KZ
authors.lastname: Hazleton
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Mason
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
authors.forename: Peter C
authors.initials: PC
authors.lastname: Tyler
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001372:Aza Compounds / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding
chemical_list: D000962:Antimalarials; D001372:Aza Compounds; D004791:Enzyme Inhibitors; D009705:Nucleosides; D010430:Pentosyltransferases; C083867:hypoxanthine-guanine-xanthine phosphoribosyltransferase
keywords: HGXPRTase; Malaria; Phosphoribosyltransferase; Protozoa; Purine salvage